Clinical translation and landscape of stimuli-responsive nanomedicines and microscale therapeutics

Stimuli-responsive materials enable temporal and spatial control over drug delivery and action. Traditional triggerable therapeutics are largely based on small molecules, like prodrugs and photodynamic therapy agents. Advances in nanotechnology and micromaterials have greatly expanded the field, as evidenced by clinically translated hyperthermia-generating iron oxide nanoparticles, radiotherapy-enhancing hafnium oxide nanoparticles, and ultrasound-responsive microbubbles. We here analyze the (pre-)clinical landscape of trigger-responsive therapeutics between 2014 and 2024, encompassing over 90 000 publications and 1000 clinical trials. External stimuli include light, ultrasound, radiation, magnetic field and temperature. Key internal stimuli are pH, redox and enzymes. Our analysis shows that light is by far the most popular external stimulus (44% of papers; 361 trials). Among internal stimuli, which account for 46% of papers (558 trials), redox and enzyme activation are the most explored ones. In recent years, interest in radiation (114 trials), ultrasound (33 trials), temperature (14 trials), and magnetic actuation (3 trials) is increasing, typically involving nano- and microscale platforms. In the second part of our paper, we examine translational trajectories and identify key barriers that are limiting the clinical progress of stimuli-responsive therapeutics. Important issues to address to help promote clinical translation include: (1) inaccurate medical need identification; (2) overly complex material design; (3) limited tissue penetration; (4) limited device accessibility; (5) economic constraints; and (6) challenging clinical adoption. We conclude by providing practical and practicable solutions to address these key limitations, going from nano- and micro-formulation design to development, translation and implementation, together aiming to increase the clinical impact of stimuli-responsive therapeutics.